A Poster: Three Stages of Quality Management System Implementation and Oversight

A Poster: Three Stages of Quality Management System Implementation and Oversight

If I could summarize in one page the most important lessons I have learned in pharmaceutical Quality Assurance over the last 40 years, this is it.

This acknowledges that putting words in a procedure does not mean they will be put into action or be effective.

The responsibility of Quality Assurance is to ensure that an effective Quality Management System (QMS) is put in place procedurally, is in use behaviorally, and is in control measurably.

The responsibility of Management is to enable each element of the QMS by means of an identified owner; to provide oversight through performance metrics; and to promote the QMS as a normal and valued part of the business---not to make the FDA happy or pass an inspection.

As I reflect on my pharmaceutical career and the many clients I have served over the years, the best results and most rewarding experiences were with those who embraced this concept.

My hope is for all my followers to use this simple graphic as a way to communicate a QMS implementation strategy.

I would be pleased to support your effort with details behind each of these points.

If you would like a high resolution image, please write to me at my personal email address: snyderjohn@mac.com. You have my permission  to use freely.

The QA Pharm

Part 2: Responding to FDA483 Observations and Fulfilling Commitments

Part 2: Organizing to Get the Work Done

Responding to FDA483 observations was my focus in Part 1 of this series. Responses lead to commitments, and commitments lead to changes that are intended to prevent recurrence of the underlying problem that led to the observation.

In Part 2, I share my views on getting the work done to fulfill the FDA commitments. The following have become benchmarks from those who are the best at getting the job done in a sustainable way and getting the problems behind them:

• Form teams. This might seem obvious, but forming cross functional teams representing stakeholders is often overlooked. The solution will very likely involve creating different ways of working that cross functional lines. It is a rookie mistake to think that the fix is something for the Quality Department to do on its own, or just an editorial change to a procedure. Depending on the problem, the team may need to be dedicated to allow focus, particularly if accelerated timelines are involved. Include subject-matter-experts that have the scientific, technical, and cGMP backgrounds to provide appropriate guidance.

• Use consultants judiciously. Consultants can provide valuable additional support. They should bring relevant industry experience that can help scope the project and give practical advice that keeps the project moving toward the solution. The best consultants are good listeners who can help you design the right solution that works for you. But, if the only team members that show up to meetings are the consultants, something is terribly wrong. Do not outsource your responsibility to consultants. Let them help you, but it's your company and you own the results.

• Determine the deliverables. Many teams go off the rails because they fail to determine the tangible deliverables that address the problem. You cannot grasps the degree of effort, determine the resource needs, or estimate the timeline until there is a clear vision of what "done" looks like. If you cannot describe "done," then you do not know the problem well enough.

•  Solve the problem, not just the Commitment. Make a careful assessment of what it will take to prevent recurrence of the observation, not just satisfy the specific commitment. The FDA always states in the FDA483 that the observations are just examples and are not all-inclusive. Companies are expected to determine all that is necessary to permanently resolve the problem that underlies the observation wherever it applies. Perform a root cause analysis and ensure that the solutions are operational and sustainable. That invariably involves more work that the narrow view of a specific example cited in an observation or the response given.

• Determine how you will know the problem is solved. In true fashion of a CAPA, determine how you will measure effectiveness. What will tell you that the solution worked? What will be your first sign that it did not work? Consider whether this is yet another attempt at solving the same old problem. Remember that recurring observations lead to increased levels of enforcement. Be sure you know the problem is truly solved.

• Avoid Information Technology (IT) Solutions. This may sound a bit strange, but in my personal experience, nearly every commitment made in a FDA483 response that involved an IT solution missed the commitment date by light-years. I know that it should not have to be that way. I'm just saying that in my 20 years of consulting experience, that has always been the case. Consider applying an IT solution as a later improvement, not within the commitment time line if at all possible.

• Use Project Management Principles and Tools. Quality System development work is not like a capital project where much of what is needed to estimate the time and cost is known upfront. Quality system and compliance projects are more often like exploratory surgery where a lot is learned once you open it up the patient. You may discover that multiple linking systems are affected after you start looking at the problem more deeply.  Recognize that plans will need to be adjusted along the way. Do not confuse progressive revelation with scope creep. Be adaptable. Establish plans and reports based on the work and target dates, not subjective feel-good dashboards with perpetual dates that slip. Anticipate problems with hitting the date and mitigate them before failure is a foregone conclusion. When you see that the timeline is slipping, ask for help and consider first what it will take to get back on track. Don't just keep moving the target date back as the default solution.

• Provide Infrastructure Support. Remediating compliance problems often require new ways of thinking, not just new ways of working. Compliance problems frequently go hand-in-hand with company culture problems. Progressive companies that recognize the business value of an effective Quality Management System also recognize the opportunity that regulatory inspections provide to examine its culture and values. Change management coaches can help a company adapt to the changes required to support a quality and regulatory compliance culture. Recurring compliance problems are frequently a culture problem that discounts the value of an effective Quality Management System and regulatory compliance to the business. 

• Provide Management Support. Ensure that each project team has a sponsor who is the best fit based on the functional owner of the process being remediated. Clearly identify the role of the sponsor and ensure that it includes removing obstacles such as lack of organization alignment, stalled decisions, team dysfunction, and inadequate budget. Sponsors are the champions who are willing to delve into the level of the working team to provide visible support, rather than sit on the management team and undermine their own folks at project update meetings. Being sponsors of quality system remediation projects provides a unique opportunity for function heads to understand dependent processes across functional lines.

• Establish Governance Oversight. The work associated with fulfilling commitments is tightly connected to managing risk. Thus, it is important to keep site governance councils frequently updated with progress and informed about unacceptable risks. These risks always include the risk of meeting a commitment date made to the FDA. Take commitment dates seriously. Other unacceptable conditions uncovered along the way should also be communicated to the governance body. Establish clear lines of communication and escalation between the team that actually does the work and governance. Learn how to escalate and resolve potential problems quickly. Nothing consumes the timeline as much as reluctant escalation and indecision.

• Verify that Deliverables Solve the Problem. Take an independent look to ensure the work is completed and that the tangible deliverables are in-place and in-use. This is a good role for an independent consultant. It is far better to find out for yourself that the mark was missed than for the FDA to call it to your attention as a repeated observation. Be a healthy skeptic and ask, "How do we know for sure the problem is permanently solved?"

• Revisit Commitments. Although you may have verified that the solution is in-place and in-use, revisit the problem at an appropriate time interval to ensure that the organization has not reverted to the old ways of working.

How have you managed regulatory commitments? What are your success stories? What have been epic failures, and why?

The QA Pharm

Part 1: Responding to FDA483 Observations and Fulfilling Commitments

Part 1: The FDA483 Response

In this two-part series will discuss responding to the FDA483 and getting the work done to fulfill the commitments in a sustainable way.

Unlike a Warning Letter, a response is not required--but highly advisable. It is standard industry practice to respond to FDA483 observations. Responsible companies that want to have a good relationship with the FDA respond to each observation by saying exactly how problems will be addressed.

There is plenty advice available, even from the FDA, on what constitutes a good response. For certain, the difference between a good and a poor response may differentiate how you are viewed by the FDA.

From my experience, the following are points to consider that have worked well when forming a response:

• Do you agree with the response? Stating up front that you either agree or disagree, in part or on the whole, stages the rest of the response. Think twice before you say you completely disagree especially with everything-- because the FDA will always have the regulations, industry good practice, and the facts on their side. But it is quite possible that the FDA investigator got the facts wrong or drew the wrong conclusion. This is why a close-out meeting with investigators at the conclusion of the inspection is important. It is better to straighten out the record at the close-out meeting than in the FDA483 response.

• Defend what you are doing right. The examples of violations cited in observation are just a snapshot in time. Although you may not be proud of what was found, the finding may not be representative of the current state of control. The example may pre-date significant improvements that you have made on your own initiative, although they may be in progress and not fully implemented. Be sure to give yourself credit for such improvements. The last thing you want to do is give the impression that the FDA was the first to call a problem to your attention.

• Take product lot numbers seriously. When the FDA mentions specific lot numbers associated with a problem, it immediately puts you in the position of having to defend why those lots are still on the market, and why you have not shut down manufacturing associated with that product, process, or facility. Put your best minds and writers to work to lay out the defense of your release decision and the state of control. Be objective and use data. If you come to the conclusion, albeit late in the game, that the product should be recalled, seriously consider the right thing to do. Also take into account causing a critical drug shortage, because the FDA will work with you to avoid a shortage while you resolve inspection-related problems.

• Defend State of Control. Some types of observations paint a picture of being out of control, particularly when it is associated with validation, sterility assurance, potency, content uniformity--you know--the SISPQ issues. Also, taken collectively, observations that run the gamut of the quality system can indicate a precarious state of control. Take your best, realistic, honest shot at how you know you are manufacturing and distributing a safe, quality product. And, for goodness sake, do not--I repeat--do not anchor your defense that there have been no complaints or dead bodies in the street. Meeting all end product specifications may be the best defense you have if statistically treated, but be aware that a "final product spec" defense will always peg you as a 1970s time traveler.

• Commit to Action. Address the specific issues that were called to your attention, but do not stop there. Carefully determine the root causes of the issues cited in the observations. There will not always be a one-to-one relationship of root cause to observation. Nonetheless, run the problem to ground and understand what is behind the problem. Determine the action required to prevent the reoccurrence of the problem cited. Undoubtedly, the solution will require changes in multiple areas at the system level. Be sure to convey that you are taking system-level action, not just addressing the superficial, specific examples. Remember, observations are just examples. Indicate the action you promise to take and target completion date. Be clear in advance what "done" looks like and the specific deliverables that will provide the evidence of successful completion.

• Commit to Developing Appropriate Action. If you do not know exactly what all is necessary to fix the problem, it is completely acceptable to indicate that the scope of activities and target dates will be established in a plan to be provided later. But state in the response when the plan will be completed and provided. Major milestones and target month are usually acceptable in a follow-up communication.

• Recognize the Minimalism. Very likely you have taken a minimum essential approach to the commitment. By the time all the internal reviewers have edited the response, you have pared down the work to something manageable for normal business. However, the work associated with FDA inspection observations is not normal business. The scope of the actual work required to prevent recurrence of the observation may be more than expected when you actually delve into the root cause and prevent recurrence through systemic changes. 

• Provide Realistic Target Dates. There is always a balance between showing responsiveness with aggressive target dates and over committing to unrealistic dates. When dealing with operational and quality system problems, there may be more work involved than meets the eye. Some problems may require engineering studies or process development in order to understand the right approach to take when solving a problem. Take time to really think through all that is involved in order to provide realistic target dates. You don't want to go back to the FDA--at least not too often--to revise target dates. Do inform the FDA of changes in completion dates. Don't let a broken promise be a surprise when they return to reinspect. It's far better to inform them in advance.

• Engage Your Internal Associates. I cannot tell you how often I discover the situation where commitments and target dates were given to the FDA in very well written responses, but those who carry out the work were not involved--even totally clueless. It's best to involve those who have to fulfill the commitments in the actual writing of the response. Time is of the essence when preparing a response, but cutting out those who actually do the work will always uncover significant execution issues at the worse possible time.

• Take FDA Suggestions. When the FDA makes a suggestion about retaining a GMP consultant to assess your overall quality system and help you to improve--take the suggestion. This recommendation usually comes in Warning Letters where the FDA has come to the conclusion from the breadth of problems and recurring problems that there is no confidence in your Quality Unit or Management Oversight. Consider such a recommendation as a direct hit and taking on water, not just a shot across the bow. So be responsive and act accordingly.

What is your experience with preparing regulatory observation responses? What has worked well? What has not worked well?

In Part 2 I will talk about organizing to get the work done to fulfill commitments.

The QA Pharm

The Quality Management Triad: a Model for Performance Sustainability

Establishing a sustainable Quality Management System that helps a company to become an anticipating, rather than a reactive organization requires intentional effort to bring three essential element together. I call these elements the Quality Management Triad.

The first part is Quality Governance, this is the body that provides:

• Vision—the aspirational view of the future, and how Quality Management is integral to the business strategy for operational performance and continuous product availability to patients;

• Leadership—the top business unit and functional heads who motivate, align, plan, and engage the organization toward its quality goals;

• Standards—endorse the policies and norms, which establish the quality requirements—the interpretation of laws and regulations to your operation—the “what” is required;

• Oversight—the communication channels and forums that give Leadership visibility to product quality and compliance risks and trends—in order to make effective data-driven decisions—and provide Leadership the means to exercise management responsibility.

The second part is the Pharmaceutical Quality System (which is the ICH Q10 term for the Quality Management System). The Pharmaceutical Quality System—or PQS:

•  Management System—the totality of policies, standards, processes that directs and controls activities with regard to quality;

• Processes—to ensure consistency and intentional ways of working when applying the standards to your operation—and to control variables, including the human variable;    

• State of Control—quality is about controlling variation, and the Pharmaceutical Quality System provide the capability of self-detecting and self-correcting problems and give us a clear picture of our current state of control.

• Continuous Improvement—knowing the top regulatory compliance risks at any give time and having project teams directed toward resolving them with verifiably effective solutions.

The third part is Quality System Ownership, which is the specific application of the concept of Business Process Ownership that sets expectations and accountability for managing the constituent parts of the Pharmaceutical Quality System:  Ownership responsibility includes:

• Execution—they manage the daily operation of the quality processes described in procedures and ensure procedures are effective;

• Maintenance—they ensure that the quality process remains current with regulatory requirements and industry practices; and remain applicable to your changing business;

• Performance—they measure how well the process is working and identify problems with the process, and problems that the process detects—and always seeking ways to meet the requirements in the most efficient way.

• Escalation—they identify unacceptable conditions or events that puts the patient and the business at risk—and take the immediate actions necessary to mitigate the risk, and make recommendations for permanently solving the problem.

At the center is the Quality function whose responsibility it is to engineer the processes for these three parts, and to ensure that they work—and work together effectively.

To be clear—quality is everyone’s responsibility. Much like Safety is everyone’s responsibility, it is the Quality function’s responsibility to establish the ways and means for the Quality Management Triad; and ensure effectiveness.

Why is The Quality Management Triad important?

The pharmaceutical industry is a dynamic business environment.  Acquisitions, operational realignment, portfolio changes, manufacturing relocation, facility re-purposing, and organization restructuring and integration are among the strategies to increase stockholder value. These continual changes impact the Quality Management System, and like any other aspect of the operation, it must be managed to remain effective and relevant.

Take this hypothetical example: 

A single-ingredient, solid-oral tablet manufacturer that constructed a dedicated facility for their new product.

Later, high-potency, multi-ingredient tablets were introduced into this facility as line extensions. The facility was then expanded to manufacture oral liquids and eventually retrofitted to produce oral suspension products.

Plans were being made to introduce parenteral drugs into the facility when the decision was made to enter into an agreement with a contract manufacturing operation—a CMO—for that technology, which was the firm’s first venture into a third-party partnership.

All the while, volumes were increasing, markets became global and the company turned to a twenty-four seven operation to keep up with demand. The increased profitability was directed toward the development of promising new drugs, while operating expenses were reduced and tightly controlled to fund new initiatives.

While this was great news for investors and employees, an unintended consequence was quietly undermining the business. The Pharmaceutical Management System had not evolved with the business, and was no longer capable of reliably detecting and managing product quality and compliance risks.

“Loss of management control” was the underlying theme of the series of FDA483s and the eventual warning letter when the site was fraught with recurring manufacturing deviations, missed target dates, and ineffective solutions promised to the Agency.

Although this is a hypothetical case, many people identify with some parts of this story when I share it.

Unfortunately, the Quality Management System is often viewed as a resilient tome of instructional content with little susceptibility to changes in the business environment. Nothing could be farther from reality.

Quality professionals across the industry who have looked back at their past quality problems and regulatory enforcement action, say—ironically—that their Quality Management System was a victim of their success.

Whatever the environment, the Quality Management System must be managed to ensure that it is Fit-for-Purpose and that it continually serves and protects the business.

The Quality Management Triad is a key element of a business strategy to sustain performance and ensure a continuous supply of quality product to patients.

The QA Pharm

"Murder for Diversion" The first Jacob Blake Pharma Mystery by John Snyder

I started the QAPharm Blog three years ago as a creative outlet to share my perspective on the pharma industry and the quality assurance profession. I have appreciated my faithful readers from dozens of countries around the world.

As many of my readers have noted, I took a hiatus from blogging for a year. During that time I wrote the first "whodunit" murder mystery ever set the the pharmaceutical industry.

Murder for Diversion by John Snyder is the first Jacob Blake murder murder mystery, and it is available at Amazon for your Kindle. I hope you enjoy it.

Just like my blog, it is infused with my experience in the pharmaceutical industry, but it is a true work of fiction. All places, events and characters are the product of my imagination. 

Here's a little bit about my book and protagonist Jacob Blake.

Jacob Blake is reinventing himself.  He's an expert in pharmaceutical manufacturing quality, but his career and his life is at a crossroads, when an uncle dies and leaves him property in, of all places, Texas. He drives cross-country, thinking that maybe this is a sign, a direction for him to go.  But his old life calls, and his ex-boss and nemesis in Philadelphia asks him to take a look at a mystery.  His first inclination is to not look back, then his old boss is suddenly dead, leading Jacob into a world of shady dealings, and murder.  This is the first in a planned series looking at what the public doesn't know about how the drugs they take every day are made and following a character in his journey of re-creation and life renewal. 

So, if the book was written by John Snyder and I am QA Pharm, then QA Pharm must be John Snyder.

I hope you enjoy the book and continue to check in with me here at The QA Pharm. 

I am very happy to know you.

John Snyder
The QA Pharm

The Top Ten Warning Letter Observations about the Pharmaceutical Quality Unit

The responsibilities of the Pharmaceutical Quality Unit are defined in the CGMPs and practices clarified in guidance documents. (See The QA Pharm, August 7, 2011.)

Just as it is with any legal matter, case histories help us understand how the law is applied in specific situations. That’s the reason it is a good practice to regularly review Warning Letters on the FDA website.

Here’s my condensed list of issues the FDA has had with the Quality Unit as seen in Warning letter observations.

This is the list you don’t want to be on.

1.    QU failed to establish a system to ensure that…[fill in the blank for anything that went wrong]

2.    QU failed to document the responsibilities applicable to the quality control unit in procedures, and fully perform these responsibilities.

3.    The personnel performing laboratory tests… were not trained.

4.    QU failed to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products.

5.    QU failed to fully perform and/or document the review of batch production records to determine compliance with all established, approved written procedures before a batch is released or distributed.

6.    QU failed to ensure that all tests are in conformance with the established specifications and that these are met prior to the release of drug products for distribution.

7.    QU did not review production records to assure that no errors had occurred or, if errors had occurred, that they had been fully investigated, conclusions made and followed-up.

8.    QU failed to investigate complaints involving the possible failure of a drug product to meet any of its specifications.

9.    Failure to submit NDA-Field Alert Reports (FARs) within three (3) working days of receipt of information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug products

10.  And my personal favorite…a designated QU has not been established.

The QA Pharm

Are Commitments Made to FDA to be taken Seriously?

Responses to FD483’s and Warning Letters are usually fully of commitments. They involve “what” will be done to correct compliance problems, and “when” it will be done. FDA has even started to ask “how” they will be done, meaning—Do you have the resources to do the work?

If these questions are not fully addressed in the FD483, then FDA will say so in the subsequent Warning Letter in the part where they acknowledge receipt of the firm’s FD483 response—and the inadequacy of it.

My first point is that there is no excuse for an inadequate response to an FD483 or a Warning Letter.

There are plenty of Warning Letters on the FDA website that provide examples of poor responses and what the FDA thinks about them. There’s no excuse for not knowing how to respond. (Also see The QA Pharm, October 10, 2010.)

Reasons for poor responses are:

·       Arrogance (What problem? Let me explain why we have no problem.)

·       Bad advice from house counsel (Dance around the edges, but never admit having a problem.)

·       Minimalism (Commit as little as possible and don’t look for other problems.)

·       Being far removed from the problem (Responses are so bad that it makes your technical insiders embarrassed.)

·       No root cause (Doing lots of stuff, but very little directed toward the real problem.)

·       Poor writing skills. (Difficult to follow the story line, because you have no idea what you want to say.)

My second point is never, ever miss a commitment date.

If anyone were to ask the leadership of any company under FDA enforcement action whether FDA commitments should be taken seriously, the response would be a resounding “Of course.”

Yet actions say differently.

It continues to amaze me how many companies miss commitment dates. And even more amazing—the senior management had no clue they had missed them. This is totally unconscionable and an indicator why the company has compliance trouble in the first place.

Reasons for missing commitment dates are:

·       No system to track responses and commitments

·       Responses and commitments are buried with hundreds of other TrackWise records, most of which are also overdue

·       Overly project managed until there is more planning than action

·       Lack of visibility as a standing agenda item in the management boardroom

·       No accountability at any level for results

·       Agency responses are kept a secret, or not sufficiently distributed to employees

·       Those responsible for doing the work had no idea that a commitment was made

The best way to think about the seriousness of a commitment to the FDA is to remember that the FDA already suspects a noncompliant firm to be untrustworthy—or at best they are neutral about their credibility. To not deliver on a commitment date just confirms their suspicion and puts the relationship between the firm and FDA on shaky ground.

Not providing an adequate response simply indicates being out of the mainstream of pharmaceutical industry know-how. And missing commitment

dates is nothing less that breaking a promise.

How would you feel if you were not taken seriously?

The QA Pharm